Field of the Present Invention
The present invention relates to a process for rapidly preparing a derivatized cyclodextrin with limited amounts of side products. In some embodiments, the process is conducted continuously or semi-continuously using flow-through equipment.
Background Art
Hydrophobic, hydrophilic, polymerized, ionized, non-ionized and many other derivatives of cyclodextrins have been developed, and their use in various industries has been established. Generally, cyclodextrin derivatization proceeds via reactions in which —OH groups at the 2-, 3-, and/or 6-position of the amylose rings of a cyclodextrin are replaced with substituent groups. Substituents include neutral, anionic and/or cationic functional groups.
Known cyclodextrin derivatives include, but are not limited to, sulfoalkyl ether cyclodextrin derivatives, alkylether cyclodextrin derivatives (e.g., methyl, ethyl and propyl ether cyclodextrins), hydroxyalkyl cyclodextrin derivatives, thioalkyl ether cyclodextrin derivatives, carboxylated cyclodextrin derivatives (e.g., succinyl-β-cyclodextrin, and the like), sulfated cyclodextrin derivatives, and the like. Cyclodextrin derivatives having more than one type of functional group are also known, such as sulfoalkyl ether-alkyl ether-cyclodextrin derivatives (see, e.g., WO 2005/042584 and US 2009/0012042, each of which is hereby incorporated by reference in its entirety). In particular, cyclodextrin derivatives having 2-hydroxypropyl groups and/or sulfoalkyl ether groups have found use in pharmaceutical formulations.
A sulfobutyl ether derivative of β-cyclodextrin (“SBE-β-CD”) has been commercialized by CyDex Pharmaceuticals, Inc. as CAPTISOL® and ADVASEP®. The anionic sulfobutyl ether substituent improves the aqueous solubility and safety of the parent β-cyclodextrin, which can reversibly form complexes with active pharmaceutical agents, thereby increasing the solubility of active pharmaceutical agents and, in some cases, increase the stability of active pharmaceutical agents in aqueous solution. CAPTISOL® has a chemical structure according to Formula X:
where R is (—H)21-n or ((—CH2)4—SO3−Na+), and n is 6 to 7.1.
Sulfoalkyl ether derivatized cyclodextrins (such as CAPTISOL®) are typically prepared using batch methods as described in, e.g., U.S. Pat. Nos. 5,134,127, 5,376,645 and 6,153,746, each of which is hereby incorporated by reference in its entirety.
Sulfoalkyl ether cyclodextrins and other derivatized cyclodextrins can also be prepared according to the methods described in the following patents and published patent applications: U.S. Pat. No. 3,426,011, U.S. Pat. No. 3,453,257, U.S. Pat. No. 3,453,259, U.S. Pat. No. 3,459,731, U.S. Pat. No. 4,638,058, U.S. Pat. No. 472,706, U.S. Pat. No. 5,019,562, U.S. Pat. No. 5,173,481, U.S. Pat. No. 5,183,809, U.S. Pat. No. 5,241,059, U.S. Pat. No. 5,536,826, U.S. Pat. No. 5,594,125, U.S. Pat. No. 5,658,894, U.S. Pat. No. 5,710,268, U.S. Pat. No. 5,756,484, U.S. Pat. No. 5,760,015, U.S. Pat. No. 5,846,954, U.S. Pat. No. 6,407,079, U.S. Pat. No. 7,625,878, U.S. Pat. No. 7,629,331, U.S. Pat. No. 7,635,773, US2009/0012042, JP 05001102 and WO 01/40316, as well as in the following non-patent publications: Lammers et al., Red. Trav. Chim. Pays-Bas 91:733 (1972): Staerke 23:167 (1971), Adam et al., J. Med. Chem. 45:1806 (2002), Qu et al., J. Inclusion Phenom. Macrocyclic Chem. 43:213 (2002), Tarver et al., Bioorg. Med. Chem. 10:1819 (2002), Fromming et al., Cyclodextrins in Pharmacy (Kluwer Academic Publishing, Dordrecht, 1994), Modified Cvclodextrins: Scaffolds and Templates for Supramolecular Chemistry (C. J. Easton et al. eds., Imperial College Press, London, UK, 1999), New Trends in Cyclodextrins and Derivatives (Dominique Duchene ed., Editions de Santé, Paris, FR, 1991), Comprehensive Supramolecular Chemistry 3 (Elsevier Science Inc., Tarrytown, N.Y.), the entire disclosures of which are hereby incorporated by reference.
Generally, processes to prepare cyclodextrin derivatives are batch processes, in which a reaction vessel is charged with reagents for a specific amount of time and temperature, and the reaction and purification are performed in a step-wise manner. Process conditions significantly impact the structure and associated properties of a cyclodextrin derivative prepared therefrom. For example, the process conditions can alter the average degree of substitution, the distribution of substitution, the regiochemistry of substitution (i.e., the substitution pattern), and combinations thereof. Process conditions that can be controlled and varied include reaction time, temperature, stoichiometry, pH, rate of agitation, concentration, and the like. In addition to being costly and time-consuming, cyclodextrin derivatives prepared by batch processes also require significant purification due to, e.g., the breakdown of reagents and the formation of side products.
For example, sulfoalkyl ether cyclodextrins as disclosed in, e.g., U.S. Pat. No. 5,134,127 are made by treating an unsubstituted α-, β-, or γ-cyclodextrin with an alkyl sultone in the presence of a base. Because the underivatized cyclodextrin is a nephrotoxin, and alkyl sultones are also toxic, it is desirable that residual alkyl sultone and underivatized cyclodextrin levels be as low as possible in the product. U.S. Pat. No. 6,153,746 provides a batch method for producing sulfoalkyl ether cyclodextrins that contain low amounts of both residual cyclodextrin and alkyl sultone materials. However, the process disclosed therein relies upon both a slow, step-wise addition of alkyl sultone and a lengthy degradation step in which residual alkyl sultone is slowly degraded under basic conditions.